Huntington's Disease Repeat Instability and Pathogenesis

Summary

Principal Investigator: Vanessa Wheeler
Affiliation: Harvard University
Country: USA
Abstract: Huntington's disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a polymorphic CAG repeat tract beyond a threshold of ~ 36 units. The expanded CAG repeat is translated into a polyglutamine stretch at the amino-terminus of the huntingtin protein, triggering cell death in a subset of neurons in the striatum and cortex. The expanded CAG repeat also exhibits dramatic instability in the germline and in somatic tissues. The long-term goals of this research are to elucidate the molecular pathways that underlie the instability of the HD CAG repeat and the specific neurodegeneration triggered by mutant huntingtin. In HD knock-in mice, which accurately recapitulate the human HD mutation, the Msh2 gene is a modifier of repeat instability and an early striatal phenotype. In this study we will test the hypothesis that Msh2 acts in the mismatch repair pathway to modify CAG repeat instability and early phenotypes in HD knock-in mice. We will perform genetic crosses with mice deficient in specific mismatch repair genes and mouse line carrying a mutation in Msh2's ATPase domain. These experiments will provide mechanistic insight into Msh2's role in CAG repeat instability and phenotypic expression of the mutant HD allele. To determine whether candidate DMA repair genes are modifiers of the age of onset of HD in humans genetic association studies will be performed using 'extreme' individuals with onset ages deviating from values predicted by CAG repeat size. To gain further insight into the mechanism by which Msh2 modifies repeat instability and early striatal disease in the mouse we will generate a conditional knockout of the Msh2 gene using the Cre-loxP system. We will specifically inactivate Msh2 in forebrain neurons using a Camklla- driven Cre transgene to test the hypothesis that Msh2 acts in striatal neurons to modify instability and early phenotypes. Together, these studies will provide insight into mechanisms of repeat instability and pathogenesis, leading to rational therapeutic strategies aimed at slowing or halting this devastating disease.
Funding Period: 2005-09-01 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington's disease knock-in mice
    Alejandro Lloret
    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
    Hum Mol Genet 15:2015-24. 2006
  2. pmc Factors associated with HD CAG repeat instability in Huntington disease
    V C Wheeler
    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
    J Med Genet 44:695-701. 2007
  3. pmc Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes
    Ella Dragileva
    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston MA 02114, USA
    Neurobiol Dis 33:37-47. 2009
  4. pmc Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset
    Meera Swami
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
    Hum Mol Genet 18:3039-47. 2009
  5. pmc Estimating the probability of de novo HD cases from transmissions of expanded penetrant CAG alleles in the Huntington disease gene from male carriers of high normal alleles (27-35 CAG)
    Audrey E Hendricks
    Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA
    Am J Med Genet A 149:1375-81. 2009
  6. pmc Stoichiometry of base excision repair proteins correlates with increased somatic CAG instability in striatum over cerebellum in Huntington's disease transgenic mice
    Agathi Vassiliki Goula
    Department of Neurobiology and Genetics, Institute of Genetics and Molecular and Cellular Biology, UMR 7104 CNRS INSERM UdS, Illkirch, France
    PLoS Genet 5:e1000749. 2009

Scientific Experts

  • Vanessa Wheeler
  • Audrey E Hendricks
  • Ella Dragileva
  • Marcy E MacDonald
  • Tammy Gillis
  • Richard H Myers
  • Meera Swami
  • Agathi Vassiliki Goula
  • Kathryn L Lunetta
  • Allison Teed
  • Alejandro Lloret
  • Edith T Lopez
  • Yvon Trottier
  • Tiffany Massood
  • Raju Kucherlapati
  • Brian R Berquist
  • Jeanne C Latourelle
  • L Adrienne Cupples
  • David M Wilson
  • James F Gusella
  • Winfried Edelmann
  • Audrey Hendricks
  • Karine Merienne
  • Errol C Friedberg
  • Jayalakshmi Mysore
  • Edith Lopez
  • Elisa Fossale
  • Janice Espinola

Detail Information

Publications6

  1. ncbi Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington's disease knock-in mice
    Alejandro Lloret
    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
    Hum Mol Genet 15:2015-24. 2006
    ..Our findings set the stage for defining disease-related genetic pathways that will ultimately provide insight into disease mechanism...
  2. pmc Factors associated with HD CAG repeat instability in Huntington disease
    V C Wheeler
    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
    J Med Genet 44:695-701. 2007
    ..The instability of the HD disease allele in male intergenerational transmissions is reflected in the variability of the CAG repeat in DNA from the sperm of male carriers of the HD gene...
  3. pmc Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes
    Ella Dragileva
    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston MA 02114, USA
    Neurobiol Dis 33:37-47. 2009
    ....
  4. pmc Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset
    Meera Swami
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
    Hum Mol Genet 18:3039-47. 2009
    ....
  5. pmc Estimating the probability of de novo HD cases from transmissions of expanded penetrant CAG alleles in the Huntington disease gene from male carriers of high normal alleles (27-35 CAG)
    Audrey E Hendricks
    Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA
    Am J Med Genet A 149:1375-81. 2009
    ..These estimates may be useful in genetic counseling for male high normal allele carriers...
  6. pmc Stoichiometry of base excision repair proteins correlates with increased somatic CAG instability in striatum over cerebellum in Huntington's disease transgenic mice
    Agathi Vassiliki Goula
    Department of Neurobiology and Genetics, Institute of Genetics and Molecular and Cellular Biology, UMR 7104 CNRS INSERM UdS, Illkirch, France
    PLoS Genet 5:e1000749. 2009
    ..We propose that the stoichiometry of BER enzymes is one critical factor underlying the tissue selectivity of somatic CAG expansion...